Insulin is a polypeptide hormone secreted by β-cells of the pancreas and consists of two polypeptide chains, A and B, which are linked by two inter-chain disulphide bridges. Furthermore, the A-chain features one intra-chain disulphide bridge.
The hormone is synthesized as a single-chain precursor of proinsulin (preproinsulin) consisting of a prepeptide of 24 amino acid followed by proinsulin containing 86 amino acids in the configuration: prepeptide B-Arg Arg-C-Lys Arg-A, in which C is a connecting peptide of 31 amino acids. Arg-Arg and Lys-Arg are cleavage sites for cleavage of the connecting peptide from the A and B chains to form the two-chain insulin molecule. Insulin is essential in maintaining normal metabolic regulation.
The hormone is secreted as defined hexamers which dissociate by dilution firstly into dimers and secondly into monomers. The active hormone is the insulin monomer. Destabilization of the insulin hexamer and/or the insulin dimer results in fast acting insulins like B28 Asp human insulin which is disclosed in EP 214826.
Currently, the treatment of diabetes, both type 1 diabetes and type 2 diabetes, relies to an increasing extent on the so-called intensive insulin treatment. According to this regimen, the patients are treated with multiple daily insulin injections comprising one or two daily injections of a long acting insulin to cover the basal insulin requirement supplemented by bolus injections of a fast acting insulin to cover the insulin requirement related to meals.
Because diabetic patients are treated with multiple daily injections including protracted insulin supplied with multiple injections of a fast acting insulin, a combination of fast and long acting insulin in one injection will potentially save many injections. WO 2003/094951 discloses mixtures of a fast acting insulin analogue insulin aspart (B28Asp human insulin) and insulin detemir (LysB29 (Nε-tetradecanoyl) desB30 human insulin). However, mixtures of fast acting and long acting insulin analogues may suffer of a limited mixability resulting in that the fast acting insulin becomes less fast acting and the long acting insulin becomes less long acting.
It is the object of the present invention to provide improved fast acting insulins which have improved properties over the known fast acting insulins with respect to mixability with soluble, long acting insulin analogues.